ω-Aryl-12,13(e)-didehydro-13,14-dihydro-PGD compounds

ABSTRACT

Prostaglandin analogs with the following cyclopentane ring structure: ##STR1## are disclosed along with intermediates useful in their preparation and processes for their preparation. These analogs are useful for some of the same pharmacological purposes as the prostaglandins, particularly and especially as blood platelet aggregation inhibitors.

The present application is a divisional application of Ser. No. 809,249, filed June 23, 1977, now U.S. Pat. No. 4,142,052 issued Feb. 27, 1979; which is a divisional application of Ser. No. 614,244, filed Sept. 17, 1975, now pending. Likewise, U.S. Ser. No. 809,248, filed June 23, 1977, now U.S. Pat. No. 4,099,014 issued on July 4, 1978, is a divisional application of Ser. No. 614,244.

The present invention relates to prostaglandin analogs for which the essential material constituting a disclosure therefor is incorporated by reference here from U.S. Pat. No. 4,099,014. 

I claim:
 1. A prostaglandin analog of the formula ##STR2## WHEREIN ##STR3## wherein Y is ═CH--CH₂ --; wherein Z₄ is(1) cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, (2) cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, (3) cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --, (4) --(ch₂)₃ --(ch₂)_(g) --CF₂ --, or (5) --(CH₂)₃ --(CH₂)_(g) --CH2--,wherein g is one, 2, or 3; Wherein M₁ is ##STR4## wherein R₅ and R₆ are hydrogen or methyl, with the proviso that one of R₅ and R₆ is methyl only when the other is hydrogen; Wherein L₁ is ##STR5## or a mixture of ##STR6## wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being the same or different, with the proviso that one of R₃ and R₄ is hydrogen or fluoro only when the other is hydrogen or fluoro; wherein Z₃ is oxa or methylene wherein T is chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive, and s is zero, one, 2, or 3, the various T's being the same or different, with the proviso that not more than two T's are other than alkyl, with the further proviso that Z₃ is oxa only when R₃ and R₄ are hydrogen or methyl, being the same or different; and wherein R₁ is hydrogen, alkyl of one to 12 carbon atoms, inclusive, cycloalkyl of 3 to 10 carbon atoms, inclusive, aralkyl of 7 to 12 carbon atoms, inclusive, phenyl, phenyl substituted with one, two, or three chloro or alkyl of one to 3 carbon atoms, inclusive, or a pharmacologically acceptable cation.
 2. A compound according to claim 1, wherein M₁ is ##STR7##
 3. A compound according to claim 1, wherein M₁ is ##STR8##
 4. A compound according to claim 3, wherein ##STR9##
 5. A compound according to claim 4, wherein Z₃ is methylene.
 6. A compound according to claim 5, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 7. A compound according to claim 6, wherein Z₄ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 8. A compound according to claim 7, wherein g is one.
 9. A compound according to claim 8, wherein R₅ and R₆ are both hydrogen.
 10. A compound according to claim 9, wherein R₃ and R₄ are both hydrogen.
 11. 2,2-Difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD₂, a compound according to claim
 10. 12. 17-Phenyl-18,19,20-trinor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD₂, a compound according to claim
 10. 13. cis-4,5-Didehydro-17-phenyl-18,19,20-trinor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD₁, a compound according to claim
 10. 14. A compound according to claim 6, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 15. A compound according to claim 14, wherein g is one.
 16. A compound according to claim 15, wherein R₅ and R₆ are both hydrogen.
 17. A compound according to claim 15, wherein R₃ and R₄ are both hydrogen.
 18. 2,2-Difluoro-17-phenyl-18,19,20-trinor-13,14-dihydro12,13(E)-didehydro-9-deoxy-PGD₁, a compound according to claim
 17. 19. 17-Phenyl-18,19,20-trinor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD₁, a compound according to claim
 17. 20. A compound according to claim 4, wherein Z₃ is oxa.
 21. A compound according to claim 20, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 22. A compound according to claim 21, wherein Z₄ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 23. A compound according to claim 22, wherein g is one.
 24. A compound according to claim 23, wherein R₅ and R₆ are both hydrogen.
 25. A compound according to claim 24, wherein R₃ and R₄ are both hydrogen.
 26. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD₂, a compound according to claim
 25. 27. 16-Phenoxy-17,18,19,20-tetranor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD₂, a compound according to claim
 25. 28. cis-4,5-Didehydro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD₁, a compound according to claim
 25. 29. A compound according to claim 21, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 30. A compound according to claim 29, wherein g is one.
 31. A compound according to claim 30, wherein R₅ and R₆ are both hydrogen.
 32. A compound according to claim 31, wherein R₃ and R₄ are both hydrogen.
 33. 16-Phenoxy-17,18,19,20-tetranor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD.sub.1, a compound according to claim
 32. 34. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-13,14-dihydro-12,13(E)-didehydro-9-deoxy-PGD₁, a compound according to claim
 32. 35. A compound according to claim 3, wherein ##STR10##
 36. A compound according to claim 35, wherein Z₃ is methylene.
 37. A compound according to claim 36, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 38. A compound according to claim 37, wherein Z₄ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 39. A compound according to claim 38, wherein g is one.
 40. A compound according to claim 39, wherein R₅ and R₆ are both hydrogen.
 41. A compound according to claim 40, wherein R₃ and R₄ are both hydrogen.
 42. 2,2-Difluoro-17-phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₂, a compound according to claim
 41. 43. 17-Phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₂, a compound according to claim
 41. 44. 17-Phenyl-18,19,20-trinor-cis-4,5-Didehydro-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₁, a compound according to claim
 41. 45. A compound according to claim 37, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 46. A compound according to claim 45, wherein g is one.
 47. A compound according to claim 46, wherein R₅ and R₆ are both hydrogen.
 48. A compound according to claim 47, wherein R₃ and R₄ are both hydrogen.
 49. 2,2-Difluoro-17-phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₁, a compound according to claim
 48. 50. 17-Phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₁, a compound according to claim
 48. 51. A compound according to claim 48, wherein Z₃ is oxa.
 52. A compound according to claim 51, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 53. A compound according to claim 52, wherein Z₄ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis--CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 54. A compound according to claim 53, wherein g is one.
 55. A compound according to claim 54, wherein R₅ and R₆ are both hydrogen.
 56. A compound according to claim 55, wherein R₃ and R₄ are both hydrogen.
 57. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₂, a compound according to claim
 56. 58. 16-Phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₂, a compound according to claim
 56. 59. cis-4,5-Didehydro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₁, a compound according to claim
 56. 60. A compound according to claim 52, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 61. A compound according to claim 60, wherein g is one.
 62. A compound according to claim 61, wherein R₅ and R₆ are both hydrogen.
 63. A compound according to claim 62, wherein R₃ and R₄ are both hydrogen.
 64. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₁, a compound according to claim
 63. 65. 16-Phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9,10-didehydro-9-deoxy-PGD₁, a compound according to claim
 63. 66. A compound according to claim 3, wherein ##STR11##
 67. A compound according to claim 66, wherein Z₃ is methylene.
 68. A compound according to claim 67, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 69. A compound according to claim 68, wherein Z₄ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --,
 70. A compound according to claim 69, wherein g is one.
 71. A compound according to claim 70, wherein R₅ and R₆ are both hydrogen.
 72. A compound according to claim 71, wherein R₃ and R₄ are both hydrogen.
 73. 2,2-Difluoro-17-phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9β-PGD₂, a compound according to claim
 72. 74. 17-Phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9β-PGD₂, a compound according to claim
 72. 75. cis-4,5-Didehydro-17-phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9β-PGD₁, a compound according to claim
 72. 76. A compound according to claim 68, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 77. A compound according to claim 76, wherein g is one.
 78. A compound according to claim 77, wherein R₅ and R₆ are both hydrogen.
 79. A compound according to claim 77, wherein R₃ and R₄ are both hydrogen.
 80. 2,2-Difluoro-17-phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9β-PGD₁, a compound according to claim
 79. 81. 17-Phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-9β-PGD₁, a compound according to claim
 79. 82. A compound according to claim 66, wherein Z₃ is oxa.
 83. A compound according to claim 82, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 84. A compound according to claim 83, wherein Z₄ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 85. A compound according to claim 84, wherein g is one.
 86. A compound according to claim 85, wherein R₅ and R₆ are both hydrogen.
 87. A compound according to claim 86, wherein R₃ and R₄ are both hydrogen.
 88. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9.beta.-PGD₂, a compound according to claim
 87. 89. 16-Phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9β-PGD₂, a compound according to claim
 87. 90. cis-4,5-Didehydro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9β-PGD₁, a compound according to claim
 87. 91. A compound according to claim 83, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 92. A compound according to claim 91, wherein g is one.
 93. A compound according to claim 92, wherein R₅ and R₆ are both hydrogen.
 94. A compound according to claim 93, wherein R₃ and R₄ are both hydrogen.
 95. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9.beta.-PGD₁, a compound according to claim
 94. 96. 16-Phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-9β-PGD₁, a compound according to claim
 94. 97. A compound according to claim 3, wherein ##STR12##
 98. A compound according to claim 97, wherein Z₃ is methylene.
 99. A compound according to claim 98, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 100. A compound according to claim 99, wherein Z₄ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CF₂ --.
 101. A compound according to claim 100, wherein g is one.
 102. A compound according to claim 101, wherein R₅ and R₆ are both hydrogen.
 103. A compound according to claim 102, wherein F₃ and R₄ are both hydrogen.
 104. 2,2-Difluoro-17-phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-PGD₂, a compound according to claim
 103. 105. 17-Phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-PGD₂, a compound according to claim
 103. 106. cis-4,5-Didehydro-17-phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-PGD₂, a compound according to claim
 103. 107. A compound according to claim 99, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ -- or --(CH₂)₃ --(CH₂)_(g) --CH₂ --.
 108. A compound according to claim 107, wherein g is one.
 109. A compound according to claim 108, wherein R₅ and R₆ are both hydrogen.
 110. A compound according to claim 109, wherein R₃ and R₄ are both hydrogen.
 111. 2,2-Difluoro-17-phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-PGD₁, a compound according to claim
 110. 112. 17-Phenyl-18,19,20-trinor-12,13(E)-didehydro-13,14-dihydro-PGD₁, a compound according to claim
 110. 113. A compound according to claim 97, wherein Z₃ is oxa.
 114. A compound according to claim 113, wherein s is zero or one and T is chloro, fluoro, or trifluoromethyl.
 115. A compound according to claim 114, wherein Z₄ is cis-CH═CH--CH₂ --(CH₂)_(g) --CF₂ --, cis-CH═CH--CH₂ --(CH₂)_(g) --CH₂ --, or cis-CH₂ --CH═CH--(CH₂)_(g) --CH₂ --.
 116. A compound according to claim 115, wherein g is one.
 117. A compound according to claim 116, wherein R₅ and R₆ are both hydrogen.
 118. A compound according to claim 117, wherein R₃ and R₄ are both hydrogen.
 119. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-PGD.sub.2, a compound according to claim
 118. 120. 16-Phenoxy-17,18,19,20-tetranor- 12,13(E)-didehydro-13,14-dihydro-PGD₂, a compound according to claim
 118. 121.cis-4,5-Didehydro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-PGD₁, a compound according to claim
 118. 122. A compound according to claim 114, wherein Z₄ is --(CH₂)₃ --(CH₂)_(g) --CF₂ --or --(CH₂)₃ --(CH₂)_(g) --CH₂ -.
 123. A compound according to claim 122, wherein g is one.
 124. A compound according to claim 123, wherein R₅ and R₆ are both hydrogen.
 125. A compound according to claim 124, wherein R₃ and R₄ are both hydrogen.
 126. 2,2-Difluoro-16-phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-PGD.sub.1, a compound according to claim
 125. 127. 16-Phenoxy-17,18,19,20-tetranor-12,13(E)-didehydro-13,14-dihydro-PGD₁, a compound according to claim
 125. 